The present invention relates generally to medical appliances and especially to the application of electrically charged porous patches in fluid communication with a drug medium and to a uniform system of an electrophoretic pharmaceutical delivery cuff apparatus for transdermal drug delivery.
The use of iontophoresis and electrotherapy for drug delivery has been known and recognized as an acceptable form of treatment. Prior devices utilizing iontophoresis and/or electrophoresis were unable to simultaneously treat large areas systematically in an anatomical circumference or be incorporated under casts or braces, with the exception of U.S. Pat. No. 5,344,384 to one of the co-inventors of the present invention.
Furthermore, the previously known devices did not provide the availability of multiple treatment protocols.
Many iontophoretic drug delivery devices have been described in the patent literature, including U.S. Patent Numbers:
U.S. Pat. No. 5,387,189 to Gory et al;
U.S. Pat. No. 5,358,483 to Sibalis;
U.S. Pat. No. 5,356,632 to Gross et al;
U.S. Pat. No. 5,312,325 to Sibalis;
U.S. Pat. No. 5,279,544 to Gross et al;
U.S. Pat. No. 5,167,479 to Sibalis;
U.S. Pat. No. 5,156,591 to Gross et al,
U.S. Pat. No. 5,135,479 to Siballs et al;
U.S. Pat. No. 5,088,977 to Sibalis;
U.S. Pat. No. 5,057,072 to Phipps;
U.S. Pat. No. 5,053,001 to Reller et al,
U.S. Pat. No. 4,942,883 to Newman;
U.S. Pat. No. 4,752,285 to Patelenz et al;
U.S. Pat. No. 4,734,090 to Sibalis;
U.S. Pat. No. 4,731,049 to Parsi;
U.S. Pat. No. 4,622,031 to Sibalis,
U.S. Pat. No. 4,325,367 to Tapper; and
U.S. Pat. No. 4,164,226 to Tapper.
The need to provide a broad spectrum of treatment protocols suited to the injury and/or medical condition of the patient requires a system having a high degree of drug flow controllability.
Controlled delivery of drugs through the skin by use of transdermal patches is well known in the prior art. Passive transdermal drug delivery systems provide advantages over other drug delivery methods by delivering the drug directly to the affected area. This method is advantageous over other known methods such as oral administration which necessitates absorption through the digestive tract, or intravenous drug administration which involves needles. Currently, certain patient types present serious problems to traditional IV techniques. These patients include: patients with blood disorders, immuno-compromised patients, patients with renal dysfunction, patients with vein disorders or deep set veins and small children. It is estimated that patients in the above categories represent at least 20-25% of all hospital patients. Both oral and intravenous administration involve administering high doses of drugs to the body at one time, systemically affecting the whole body with the pharmaceutical. These high levels of drug concentration in the blood can create toxic side effects. In addition, only a very small percentage of the drug reaches the affected target area in the body.
There has been a trend toward demands for new methods of self-administered prescription pharmaceuticals such as time-release oral medications and transdermal patches. Transdermal delivery provides medication specifically to the area of treatment in the exact quantities required. However, the number of passive transdermal drug delivery systems available, such as the nicotine, estrogen and nitroglycerine patches, are limited because they are effective only with small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches, forcing pharmaceutical companies to seek advanced delivery technology such as electrical assist (ionotophoresis) for large-molecule drugs.
Iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.
Many drugs have been formulated for commercial use in the pharmaceutical industry employing iontophoresis. Both passive and electrical assist transdermal drug delivery necessitate wearing transdermal patches made of synthetic substances consisting of a high co-polymer content for long periods of time, often causing skin reactions due to the body""s rejection of the membrane as being foreign to the skin. Also, most membrane patches require a specific drug designed toward use with a particular membrane for a specified limited time of usage. Iontophoresis often requires cumbersome electrical connections to external power sources, which may be stationary or portable which can confine the patient""s activity.
Patients are often required to wear casts or braces over long periods of time. This limits access to the treatment area, making additional medical treatment more difficult while the limb is immobilized. Atrophy of the underlying muscle tissue is a common problem. Because of the inaccessibility of the treatment area, drug delivery is made difficult, and traditional methods of drug delivery by injection must be used.
Therefore, it would be desirable to overcome the above-mentioned disadvantages and provide an unencumbered self-powered transdermal patch system for drug delivery that would deliver large-molecule drugs in an efficient manner directly to the affected site, even under a cast or brace, while allowing long term skin contact without causing skin irritation or allergic reaction.
Accordingly, it is a principal object of the present invention to overcome the disadvantages of prior art devices and systems and provide a transdermal drug delivery system of the general character described herein which is not subject to the aforementioned deficiencies.
A further object of this invention is to provide a transdermal drug delivery system having selective curative regimens that can be applied severally or together.
Another further object of this invention is to provide a transdermal drug delivery system that can be worn comfortably by the patient, as a lightweight, portable design that is cost effective to manufacture and does not encumber motion by the patient.
Another object of this invention is the capability to deliver any drug in a fluid medium having either a positive or a negative molecular valence through the skin, iontophoretically.
Many drugs have been formulated for use in iontophoretic systems, and others are being experimented with and developed by the pharmaceutical industry for the feasibility of their delivery via iontophoresis for commercial use (e.g., nicotine, antihistamines, beta-blocker, calcium channel blockers, non-steroidal, anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, antivirals, hormones, alpha-interferon and chemotherapeutic anti-cancer agents). Therefore, it is also an object to incorporate porous membranes having pores that can accommodate molecular drug weights from one to 50,000 Daltons, or greater.
Yet another object of this invention is to optimally produce a selected alternating positive and negative electrical charge from a controlled power source/console switch, thereby creating the electrical field polarity which is responsible for providing the xe2x80x9cionic drivexe2x80x9d mechanism needed to modulate either anode or cathode drug delivery within the patch devices. The ionic drive mechanism is the force behind the electrochemical phenomenon of iontophoresis required to propel, infuse and deliver a pharmaceutical medium in accordance with its polar molecular valence through the surface of the skin by means of electroosmosis. The success of administering the fluid medium depends on the negative or positive valence of that medium for anode or cathode delivery.
It is another object that the invention can provide electromagnetophoresis. Scientific information supports the concept that electromagnetic fields (EMFs), in combination with drug delivery, can either increase the osmotic penetration of drugs through the skin known as xe2x80x9cmagnetophoresisxe2x80x9d, or that EMFs may help accelerate the effectiveness of exogenous drugs after being introduced into the body by transdermal or hypodermic methods. Exposure to PMF (Pulsed Magnetic Field) immediately after administration of methotrexate or mitomycin C, pharmaceutical anti-tumor agents, into the cell increases eddy current stimulation induced by PMF, and the cell cycle shifts from the non-proliferative to proliferative phase, resulting in increased anti-tumor activity.
It is another object of to provide combined therapy, where the combination of magnetotherapy, electrotherapy and iontophoresis heighten the effectiveness of electrochemotherapuetic treatment to a target area used for electrochemotherapy (ECT). The combination of multiple drivers to produce an electrochemotherapeutic effect is known as xe2x80x9celectro-infusionxe2x80x9d.
It is also another object of the invention to provide a membrane electrode with a biosensing component that can detect flow rate over time and the amount of permeant flow through the skin and the membrane for the control of any number of drug permeants, severally, or in combination.
Another object of the invention is to create a membrane electrode with a layered structure comprising:
1. a microtitration foam layer in contact with a permeant supply superior to an electrode. This foam layer is intended to prevent leakage or seepage, and to ensure slow feed of the permeants traversing the porous membrane layer below; and
2. a porous electroconductive membrane layer or membranes with electroconductors; and
3. a biosensor or biosensors interconnected with the transdermal membrane junction to the skin which are placed as to allow the permeation of pharmaceutical fluids.
It is also an object of this invention to create a variety of configurations for transdermal drug delivery, whereby the patch is constructed of different sizes and shapes.
Another object of this invention is to provide an electrophoretic cuff apparatus that can fit under a cast or brace. A foam fabric can be used on the superior external surface of the apparatus, adding to patient comfort.
It is also an object of this invention to create a variety of configurations for constructing the cuff, whereby the cuff is constructed by the interconnecting of the membrane electrodes or can be constructed merely as a housing matrix for the electrodes.
Accordingly, it is a principal object of the invention to provide a transdermal patch system for drug delivery which is non-irritating to the skin while administering a broad range of drugs.
In accordance with a preferred embodiment of the invention there is provided a transdermal patch system for delivery of a pharmaceutical medium comprising:
a stored energy source for generating an electrical current;
means for generating an electromagnetic field having at least one predetermined frequency
means for activating said energy source to generate said current producing said electromagnetic field;
a layer of permeable foam for retaining therein a quantity of pharmaceutical medium exhibiting at least partial ionization; and
an electroconductive membrane disposed under said foam layer through which the pharmaceutical medium passes,
said electromagnetic field driving said ionized pharmaceutical medium by active transport through said membrane to provide drug treatment therapy via the skin.
In a preferred embodiment of the present invention the transdermal drug delivery system is provided as an unlinked patch device with an electroosmotic, electroporous membrane comprised of an inert biochemical substance which becomes actively electroosmotic when an electric charge is passed through the membrane. During iontophoresis, an electric current is passed into the membrane, and it becomes electro-bioactive enabling drug solution to be passed through the electrode membrane wall to a target area on the skin surface creating an electroporative effect.
In a preferred embodiment, the patch is self-powered by an autobiofuel cell for providing the electricity for iontophoresis through the membrane. The autobiofuel cell is comprised of a biochemical fuel cell substance creating a battery power source, causing an electric charge to be passed through the inert membrane which is saturated with a drug solution. The autobiofuel cell is activated by pressing on an xe2x80x9cactivation buttonxe2x80x9d causing a mix of chemical compounds which are released into the main fuel cell to activate the electric conductivity of the power drivers. An indicator is provided for indicating when the battery power source is low.
In another preferred embodiment, a female jack is provided on the top surface of the patch for either giving a temporary charge to the fuel cell when the battery is low or may be used on a more long-term basis for connection to an external power source. A portable 9V battery or stationary wall power pack may be supplied to accomplish the recharging.
The electric current from the autobiofuel cell or the external power source is passed through an intermediate electromagnetic/electroconductive separation plate, transmitting the power drivers for iontophoresis and/or magnetophoresis. The combination of both iontophoresis and magnetophoresis results in electroinfusion (c) by energizing the drug reservoir membrane from the autobiofuel cell or external power source, creating an electroosmotic electro-bioactive phenomenon transferring the permeant through the membrane layer to the treatment area. The separation plate prevents seepage and interaction of the autobiofuel cell fuel with the membrane and treatment area.
Control of the drug delivery with a porous membrane is difficult. Control must be accomplished by the membrane and not the skin. A completely porous membrane would have too low a transport resistance causing the skin to be the rate determining factor. Therefore, in a preferred embodiment, a dense coating layer is provided on the porous membrane support. Since most of the drugs that have to be delivered by the transdermal system are charged, the dense coating layer is provided with a mosaic structure such that it contains positive and negative fixed charges to accommodate differently charged drug solutions.
Parameters of the patch can be altered to accommodate specific needs of specific drug solutions. These parameters include: drug concentration, current density, membrane thickness and charge density of the fixed charges in the membrane.
In addition, the membrane is impregnated with a substance on the epidermal delivery layer to cause hyper-permeability of the permeant through the stratum corneum (SC) of the skin and into deeper body tissue layers. The SC is a thin layer of highly resistant tissue with the underlying viable dermis exhibiting a much lower resistance. The membrane is laced with acetylcholine, epinepherine or other stimulants to enhance permeability through the SC.
The dermal contact surface of the membrane is constructed out of substances close to the structure of human skin, based on the membranes used in artificial kidney membranes such as sulfonated polysulfone (PSF), so as to be non-irritating. In addition, the membrane can be constructed using components of bioenegineered artificial skin compounds (such as Apligrafs from Organogenesis, Inc.). This will reduce skin rejection of polymers currently used to accomplish transdermal transport of drug solutions. Alternatively, any commercially available transdermal membrane can be used with the patch (for example, IonClad R1010, R1030, R4010 or R4030 from Pall Corp., Port Washington, N.Y.). The patch can be used to treat open or closed wounds.
An electrophoretic tube port is provided on the external side of the patch for injection of a needle-less syringe to provide the drug solution as needed. Thus one type of disposable patch can be provided and filled with any of a variety of different drugs as needed. The drug solution is then transferred to and stored in a miniature reservoir in the patch. The reservoir can be provided as a foam layer for controlled microtitration. In another preferred embodiment, the patch is provided with a connection to an external, metered titration system. Alternatively, the port can be used to connect a standard IV drip bag via electrophoretic tubing.
In another embodiment of the present invention the patch is provided with a biosensor for sensing when the drug is no longer present and alerting the patient or physician via an audible or visual signal.
In still another preferred embodiment, a microswitch is provided to adjust and create electrical and electromagnetic frequencies of varying and alternating intensities and time cycles of a wide range to match the valences of the variety of drugs. The patch would be supplied with a microprocessor for storing and controlling the various settings. Drugs may be permeated through the transdermal membrane and the skin either singularly or in multiple combination, according to the programmed settings. The current density used is less than 0.5 mA/cm2 of the transdermal membrane electrode surface that is applied to the skin. Connections may also be provided for receiving input from the biosensors and controlling delivery from an external processor.
The transdermal patch of the present invention can be used in conjunction with an electrophoretic cuff apparatus which encompasses the construction of a preform applicator wrap enclosing one or more transdermal patches to pass a liquid drug medium through the skin and surface tissues. The electrical current may be supplied by the autobiofuel cell or through an external source. The applicator wrap is externally self-supported, contiguous to a body surface to form a preform wrap or cuff.
In particular, the electrophoretic cuff apparatus concerns an electrotherapy apparatus incorporated within or without a cast or orthotic brace or preform that delivers ancillary treatment modalities which are provided by an optional Neuromuscular Electrostimulation, Transcutaneous Nerve Stimulation (T.E.N.S.) and Interferential Electrotherapy component. The preform forms a xe2x80x9ccuffxe2x80x9d that can be wrapped around the body in different sizes and sections for easy treatment of large and small anatomical areas. The cuff is connected to a Velcro attachment to latch on the sections, to deliver the fluid medium and electrical charge.
The construction of the apparatus is important for regulated consistent uniform drug therapy around the circumference of a body part to increase efficiency of drug therapy application. Optionally, biosensors and an external pump regulated titration system can ensure precise regulation of drug flow transdermally through the skin and the transdermal membrane electrodes that act as a conduit reservoir for the flow of medicated permeants being supplied by a continuous source reservoir.
In addition to the application of electric energy in the present invention, a pulsed or continuous electromagnetic field is created by a separate circuit. When a medicament is added to the aqueous environment, the invention becomes a drug delivery apparatus with a variety of protocols for iontophoretic and electromagnetophoretic delivery systems.
When the cuff apparatus is not used for drug delivery, it can be applied and worn while the patient is exercising or conducting the activities of daily living.
The cuff wrap matrix is formed of waterproof, molded and flexible plastic, styrofoam or canvas-like material to accommodate a continuous hook-up for additional preform patches of various sizes and shapes, as required, to encompass the circumference of a desired target treatment area, thereby creating a xe2x80x9ccuffxe2x80x9d or wrap around any anatomical body part.
The wrap is provided with a network array of electrically conductive porous polymer membrane electrode patch devices providing a xe2x80x9ccheckerboardxe2x80x9d pattern of alternating positive and negative polarities.
The patches can be energized by galvanic and electromagnetic current drivers to propel permeant drugs through means of either iontophoresis, magnetophoresis or combined electromagnetophoresis.
A feature regarding the present invention of the electrophoretic cuff is that it can have multiple uses beyond its use for introducing drugs transdermally. Thus, the present invention provides, in a versatile fashion, a variety of therapeutic benefits and applications with electrical energy modes for nerve stimulation, pain sedation and the prevention of atrophy. Additionally, when configured as a therapeutic garment, the mode of Electrical Muscular Stimulation (EMS) can be introduced during physical therapy exercises, weight training for neurologically impaired and atrophic muscles, etc.
It should be apparent that the multi-modal nature of this apparatus covers a broad spectrum of treatment protocols, including the treating of injuries to soft tissues, as well as arthritis of joints at selected locations of the human and mammalian bodies.
The patches within the cuff provide a consistent supply of medication, to bathe the body part in a continuous fluid within a circumference, whereas other electrical transdermal drug delivery methods are not as easily accessible or applicable. This system also allows for transdermal drug treatment simultaneously to more than one location where medical attention is needed. In addition, a non-medicated fluid can also be used to moisten the porous electrodes as an electrolyte, to assist electrical conductivity when the apparatus is being used for purposes other than drug delivery.
In addition, the patch can apply continuous fluid medium from an optional external reservoir similar to intravenous (I.V.) applicators, but without the use of a hypodermic needle. The patch can be used, with or without the cuff, as an option to replace traditional methods of postoperative analgesia, such as intramuscular injections. The patch has benefits for those patients who dislike hypodermic needle injections or have medical conditions making intravenous drug delivery difficult.
Furthermore, when using the external reservoir, the delivery of drugs transdermally can be regulated and monitored through a computer chip and xe2x80x9cpumpxe2x80x9d administration system that records the titration rate, amount and dosage of medication supplied. The pump can vary the speed of introduction of the transdermal permeant at a desired rate.
The pump administration and titration mechanisms are interactively connected to biosensor detection sensors located within the transdermal membrane patch devices. Signals from the membrane electrode biosensor monitor the drug flow rate of permeant being transported through the skin as well as the membrane electrode. The pump/titration regulator receives these signals from the membrane biosensor to regulate exact controlled increments of the permeant being delivered to the surface of the skin with an even flow pressure distribution in the electrophoretic tubing and membrane electrodes in the cuff delivery system. Alternatively, a roller clamp can be used to clamp I.V. tubing to control the flow of the pharmaceutical permeant.
In view of the above, it should be apparent that the present invention provides many advantages and overcomes many of the shortcomings and disadvantages of the prior art, while providing an improved apparatus.
Additional features and advantages of the invention will become apparent from the following drawings and description.